Glutamate-mediated neurotransmission is the main form of excitatory neurotransmission in the vertebrate nervous system and is largely dependent on the proper function of the AMPA receptor, one of the most commonly found receptors in the central nervous system. The research plan outlined in this proposal will directly address how the.structures of both the AMPA receptor auxiliary subunit stargazin and the scaffolding protein PSD-95 regulate AMPA receptor sensitivity and clustering. The goal .is to obtain a 3D structure.of both stargazin and stargazin in complex with PSD-95 using two related electron microscopy approaches:-2D electron crystallography and single particle reconstructions. This research is core to the better understanding of several debilitating conditions and diseases of the central nervous system as well as learning and memory, as all of these processes are dependent on the proper function of glutamatergic neurotransmission. Overactivation of AMPARs and aberrant excitatory neurotransmission are both implicated in epilepsy, stroke, Parkinson's disease and more. A better understanding of the mechanisms underlying these diseases is essential for public health. The research outlined in this proposal directly addresses the role of AMPAR auxiliary subunit structure in relation to AMPAR function towards accomplishing this goal.